Associate Professor of Biochemisty and Molecular Biology, University of Massachusetts
S. Garman Biochemistry & Molecular Biology Web Site
Ph.D.: Harvard University
Postdoctoral training: Northwestern University
Structural biology of glycoproteins in human disease
Research in our lab focuses on structural biology. We are interested in glycoproteins, particularly those implicated in human disease. Recent structural results on three topics include:
Lysosomal storage diseases: In the lysosome, breakdown of glycoproteins and glycolipids occurs via the action of proteases, lipases, and glycosidases. Our lab is interested in the function and trafficking of lysosomal enzymes, required components in the catabolism of macromolecules. Deficiencies in these enzymes result in the accumulation of their substrates, which eventually leads to the symptoms of lysosomal storage diseases (a family containing over 40 members including Gaucher, Tay-Sachs, and Fabry diseases). These enzymes represent model systems for studying human genetics, because the associated diseases tend to be single gene rather than more complicated polygenic diseases. We have determined the x-ray crystallographic structures of two lysosomal glycosidases, α-N-acetylgalactosaminidase (α-NAGAL) and α-galactosidase (α-GAL), as well as complexes with their catalytic products. The structures revealed the locations of the hundreds of individual point mutations leading to Schindler and Fabry diseases and indicated the atomic basis for enzymatic failure in patients.
Malarial surface proteins: Through the course of its life cycle, the malaria parasite Plasmodium expresses scores of receptors on its surface. These receptors function in cell adhesion, entry into host cells, and immune system evasion. Due to their accessibility on the surface of the parasite and their functional importance, many show promise as vaccine candidates. We have solved the structure of the immunologically important portion of the vaccine candidate MSP-1, a GPI linked protein expressed on the surface of the merozoite form of the parasite. As a requirement for invasion into the red cell of a mammalian host, MSP-1 undergoes two proteolytic processing stages. We have solved the structure of the two domains anchored to the parasite membrane at the end of the invasion process. Host antibodies against these two domains confer protection against malaria infection.
Antibody-receptor interactions: Fc receptors are found on the surface of immune cells, where they couple the extreme specificity of antibodies to the specialized effector functions of different immune cells. Fc receptors bind antibodies distal to the antigen binding site on the antibody. In the case of mast cells, the high affinity IgE Fc receptor (FcεRI) binds the IgE antibody, and the appearance of specific antigens (such as allergens) causes crosslinking of the IgE:Fc receptor complexes. This crosslinking initiates a src kinase-mediated signal transduction pathway in the cell, leading minutes later to the degranulation of the mast cell and to the subsequent appearance of allergic symptoms. We have solved the crystal structures of the human IgE Fc receptor, both alone and in complex with the Fc portion of IgE.
Clark, NE, Garman, SC. The 1.9 A structure of human alpha-N-acetylgalactosaminidase: The structural basis of Schindler and Kanzaki diseases. Journal of Molecular Biology. 2009, Oct 23;393(2):435-447. [PubMed]
Ishii S, Chang HH, Kawasaki K, Yasuda K, Wu HL, Garman SC, Fan JQ. Mutant alpha-galactosidase A enzymes identified in Fabry disease patients with residual enzyme activity: biochemical characterization and restoration of normal intracellular processing by 1-deoxygalactonojirimycin. Biochem J. 2007 Sep 1;406(2):285-95. [PubMed]
Hebert DN, Garman SC, Molinari M. (2005) "The glycan code of the endoplasmic reticulum: asparagine-linked carbohydrates as protein maturation and quality-control tags." Trends Cell Biol. Jul;15(7):364-70. Review. [PubMed]
Su HP, Garman SC, Allison TJ, Fogg C, Moss B, Garboczi DN. (2005) "The 1.51-Angstrom structure of the poxvirus L1 protein, a target of potent neutralizing antibodies." Proc Natl Acad Sci U S A. Mar 22;102(12):4240-5. Epub 2005 Mar 10. [PubMed]
Ries M, Gupta S, Moore DF, Sachdev V, Quirk JM, Murray GJ, Rosing DR, Robinson C, Schaefer E, Gal A, Dambrosia JM, Garman SC, Brady RO, Schiffmann R. (2005) "Pediatric Fabry disease." Pediatrics. Mar;115(3):e344-55. Epub 2005 Feb 15. [PubMed]
Garman, S.C., and Garboczi, D.N. (2004) “The molecular defect leading to Fabry disease: structure of human α-galactosidase.” Journal of Molecular Biology, 337 (2), 319-335. [PubMed]
Garman, S.C., Simcoke, W.N., Stowers, A.W., and Garboczi, D.N. (2003) “The structure of the C-terminal domains of merozoite surface protein-1 from Plasmodium knowlesi reveals a novel histidine binding site.” Journal of Biological Chemistry, 278 (9), 7265-7269. [PubMed]
Garman, S.C. and Garboczi, D.N. (2002) “Structural basis of Fabry disease.” Molecular Genetics and Metabolism 77 (1-2), 3-11. [PubMed]
Garman, S.C., Hannick, L., Zhu, A., and Garboczi, D.N. (2002) “The 1.9 Å structure of α-N-acetylgalactosaminidase: molecular basis of glycosidase deficiency diseases.” Structure 10 (3), 425-434. [PubMed]
Garman, S.C., Sechi, S., Kinet, J.P., and Jardetzky, T.S. (2001) “The analysis of the human high affinity IgE receptor FcεRIα from multiple crystal forms.” Journal of Molecular Biology 311 (5), 1049-1062. [PubMed]
Wurzburg, B.A., Garman, S.C., and Jardetzky, T.S. (2000) “Structure of the human IgE-Fc Cε3-Cε4 reveals flexibility of the antibody effector domains.” Immunity 13 (3), 375-385. [PubMed]
Garman, S.C., Wurzburg, B.A., Tarchevskaya, S.S., Kinet, J.P., and Jardetzky, T.S. (2000) “Structure of the Fc fragment of human IgE bound to its high affinity receptor FcεRIα.” Nature 406, 259-266. [PubMed]
Garman, S.C., Kinet, J.P., and Jardetzky, T.S. (1999) “The crystal structure of the human high-affinity IgE receptor (FcεRIα).” Annual Reviews of Immunology 17, 973-976. [PubMed]
Garman, S.C., Kinet, J.P., and Jardetzky, T.S. (1998) “Crystal structure of the human high affinity IgE receptor.” Cell 95, 951-961. [PubMed]